Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas

Abstract

BackgroundThis study sheds light on cell inactivating processes with focus on the phenomenon of cell-in-cell (CIC). Cell-in-cell describes a cell process where one cell is being engulfed by another non-professional phagocyte. We determined frequency and prognostic impact of CIC structures (CICs) as well as of senescent and apoptotic cells in head and neck squamous cell carcinomas (HNSCC).MethodsThese different forms of cell inactivation as well as the proportion of proliferating and tumor cells were assessed in 169 pre-radiochemotherapy biopsies and 32 post-therapy tumor resections by immunohistochemistry of tissue microarrays. Four consecutive cancer sections were stained with antibodies specific for E-cadherin for CIC detection, cleaved caspase-3 for apoptosis, H3K9Me for senescence and Ki67 as a proliferation marker. Positive events were quantified in corresponding tumor areas.ResultsCICs were found in 55.5%, senescent cells in 67.1% and apoptotic cells in 93.3% of samples. While no prognostic impact of apoptotic and senescent cells was observed, CICs turned out to significantly influence overall-survival (p = 0.016) with a lack of CICs being prognostically beneficial. There was no correlation between CICs and apoptosis and 98.9% of CICs were negative for cleaved caspase-3.ConclusionCIC formation is a frequent event in HNSCC and a superior predictive marker compared to senescence and apoptosis. Independence of CIC and apoptosis and the adverse prognosis associated with numerous CICs lead to the assumption that CICs might take up necrotic rather than apoptotic cells preventing an adequate antitumoral immune response that would otherwise be initiated by necrotic cells through damage-associated molecular pattern molecules.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0746-z) contains supplementary material, which is available to authorized users.

TRAIL signalling promotes entosis in colorectal cancer

“…In agreement with other reports 17,19 a proportion of patients (75 of 211, 36%) showed no evidence of CICs in tumour tissues. Thus, we used the absence or presence of CICs as cut-off and classified the CRC patients in our cohort as CIC absent (CIC=0) or CIC present (CIC>0) if the median number of CICs detected across multiple biological replicas within the same tissue was equal to or greater than 0, respectively.…”

“…The presence of TP53 17 and KRAS 16 mutations increase the likelihood of cancer cells undergoing entosis. Several human malignancies including lung, head and neck, breast, colon, stomach, liver, cervical cancer and melanoma show evidence of CICs 13,[17][18][19] ; however, the clinical relevance of CICs remains to be elucidated.…”

Role of tumor cell senescence in non-professional phagocytosis and cell-in-cell structure formation

“…In general cell-in-cell structures are found both in normal tissue [ 31 ] and in tumor tissue [ 33 ]. A high rate of cell-in-cell structures in tumor tissue is a negative prognostic factor for example in breast carcinoma [ 20 , 34 ], metastasis of melanoma [ 24 ], cytology of bladder cancer [ 35 ], head and neck cancer [ 25 , 36 ], rectal cancer [ 25 ], oral squamous cell carcinoma [ 37 ] and lung adenocarcinoma [ 38 ]. In contrast, an increased incidence of homotypic cell cannibalism in ductal adenocarcinoma of the pancreas was associated with decreased metastatic potential and consequently was a positive prognostic factor [ 21 ].…”

Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma

“…The available data point to entosis as a correlate of aggressive behavior. In rectal cancer, head and neck squamous cell carcinoma (HNSCC) and in lung cancer, a CIC pattern has been associated with poor prognosis [5,7,8]. In breast cancer, the CIC pattern is more prevalent in high grade tumors [9].…”